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Transcription-replication conflicts occur when the two critical cellular machineries responsible for gene expression and genome duplication collide with each other on the same genomic location. Although both prokaryotic and eukaryotic cells have evolved multiple mechanisms to coordinate these processes on individual chromosomes, it is now clear that conflicts can arise due to aberrant transcription regulation and premature proliferation, leading to DNA replication stress and genomic instability. As both are considered hallmarks of aging and human diseases such as cancer, understanding the cellular consequences of conflicts is of paramount importance. In this article, we summarize our current knowledge on where and when collisions occur and how these encounters affect the genome and chromatin landscape of cells. Finally, we conclude with the different cellular pathways and multiple mechanisms that cells have put in place at conflict sites to ensure the resolution of conflicts and accurate genome duplication.
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http://dx.doi.org/10.3390/life11070637 | DOI Listing |
EMBO Rep
August 2025
Institute of Epigenetics and Stem Cells (IES), Helmholtz Munich, Feodor-Lynen-Strasse 21, Munich, 81377, Germany.
The CGG triplet repeat binding protein 1 (CGGBP1) binds to CGG repeats and has several important cellular functions, but how this DNA sequence-specific binding factor affects transcription and replication processes is an open question. Here, we show that CGGBP1 binds human gene promoters containing short (< 5) CGG-repeat tracts prone to R-loop formation. Loss of CGGBP1 leads to deregulated transcription, transcription-replication-conflicts (TRCs) and accumulation of Serine-5 phosphorylated RNA polymerase II (RNAPII), indicative of promoter-proximal stalling and a defect in transcription elongation.
View Article and Find Full Text PDFMethods Mol Biol
August 2025
Institut de Génétique Humaine, Université de Montpellier, CNRS, Equipe Labellisée Ligue contre le Cancer, Montpellier, France.
Cancers are characterized with altered genomes. Sequencing of thousands of cancer genomes has led to the identification of new types of complex genomic rearrangements that generate new chromosomes, known as chromoanagenesis. Chromothripsis is, to-date, the best characterized phenomenon of complex rearrangements, in which a single chromosome pulverization is followed by reassembly of broken DNA fragments in a random manner.
View Article and Find Full Text PDFInt J Radiat Oncol Biol Phys
August 2025
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. Electronic address:
Purpose: Poly ADP ribose polymerase inhibitors (PARPi) are being combined with photon and proton radiotherapy in clinical trials. We sought to investigate mechanisms of PARPi radiosensitization at varying linear energy transfer (LET) levels after observing an extreme normal tissue response in an 18-year-old with high grade glioma without a germline alteration predictive of heightened radiosensitivity treated with veliparib and proton therapy.
Experimental Design: BRCA1/2 wild-type non-cancerous and cancerous cells were treated with PARPi plus photons or protons at the entrance (ENT, dose-averaged LET [LETd] 2.
Viruses
August 2025
Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
The rabies virus (RABV) phosphoprotein (P protein) has multiple functions, including acting as the essential non-catalytic cofactor of the viral polymerase (L protein) for genome replication and transcription; the principal viral antagonist of the interferon (IFN)-mediated innate immune response; and the chaperone for the viral nucleoprotein (N protein). Although P protein is known to undergo phosphorylation by cellular kinases, the location and functions of the phosphorylation sites remains poorly defined. Here, we report the identification by mass-spectrometry (MS) of residues of P protein that are modified by phosphorylation in mammalian cells, including several novel sites.
View Article and Find Full Text PDFPLoS Pathog
August 2025
The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
Transcription-replication conflicts frequently occur at repetitive DNA elements involved in genome maintenance functions. The KSHV terminal repeats (TR) function as the viral episome maintenance element when bound by the viral encoded nuclear antigen LANA. Here, we show that transcription-replication conflicts occur at or near LANA binding sites in the TR.
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